Rong-Hua Luo

HIV-1 integrase strand transfer inhibitors (INSTIs) are pivotal to antiretroviral therapy. However, the emergence of drug-resistant mutations necessitates the development of new agents. Here, we present ACC017 as a novel INSTI candidate. ACC017 demonstrated potent activity against the laboratory-adapted HIV-1_IIIB strain (EC₅₀ = 0.59 nM; SI > 34,525) and maintained efficacy against a panel of drug-resistant strains (EC₅₀ range from 0.34 to 9.12 nM) and clinical isolated strains (EC₅₀ range from 0.11 to 1.78 nM). Mechanism of action studies confirmed its ability to inhibit the integrase enzyme (IC₅₀ = 9.19 nM) and effectively block viral genome integration. Notably, in vitro resistance selection primarily yielded D232N and R263K mutations, without the emergence of G140S/A/C/R or Q148H/R/K. This promising profile, combined with synergistic interactions with other antiretroviral drugs, positions ACC017 as a potential therapeutic option.

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) area key component of the current HIV-1 combination drug regimens. Although they exhibit potent anti-HIV-1 activity and modest toxicity, the emergence of mutant strains limits their application in clinical. Our previous research efforts contributed to the identification of compound K-5a2, which exhibits nanomolar activity in HIV-1-infected MT-4 cells. In this study, K-5a2 was shown to have a high level of anti-HIV-1 activity against various lab-adapted strains and clinical isolate strains, being comparable to ETR. Moreover, we showed the feasibility of K-5a2 as a preclinical anti-HIV-1 candidate by establishing its synergistic or additive anti-HIV-1 activity in combination with other representative anti-HIV-1 drugs and candidates. In addition, K-5a2 exhibited no inhibitory activity to the primary CYP isoforms and favorable pharmacokinetics. Taken together, its robust anti-HIV-1 potency, synergistic or additive effects with other anti-HIV drugs, and favorable pharmacokinetic and safety profiles make K-5a2 a potent alternative drug for HIV/AIDS treatment.

Latent reservoir persistence remains a major obstacle for curing human immunodeficiency virus type 1 (HIV-1) infection. Thus, strategies for the elimination of latent HIV-1 are urgently needed. As a bromodomain and extra-terminal (BET) inhibitor, BMS-986158 has been used in clinical trials for advanced solid tumors and hematological malignancies. Here, we found that BMS-986158 reactivated latent HIV-1 in three types of HIV-1 latency cells in vitro, and in combination antiretroviral therapy (cART)-treated patient-derived peripheral blood mononuclear cells ex vivo, without influencing global immune cell activation. BMS-986158 reactivated latent HIV-1 by increasing phosphorylation of CDK9 at Thr186 and promoting recruitment of CDK9 and RNA polymerase II to the HIV-1 long terminal repeat in J-Lat cells. Furthermore, BMS-986158 exerted strong synergism in reactivating latent HIV-1 when combined with prostratin and vorinostat and enhanced the antiviral activity of anti-HIV-1 drugs. Finally, BMS-986158 showed antiviral activity in an HIV-1 acute infection model, possibly by arresting the cell cycle in infected cells. Thus, these results suggest that BMS-986158 is a potential candidate for AIDS/HIV-1 therapy.

APOBEC3G is a member of the human cytidine deaminase family that restricts Vif-deficient viruses by being packaged with progeny virions and inducing the G to A mutation during the synthesis of HIV-1 viral DNA when the progeny virus infects new cells. HIV-1 Vif protein resists the activity of A3G by mediating A3G degradation. Phorbol esters are plant-derived organic compounds belonging to the tigliane family of diterpenes and could activate the PKC pathway. In this study, we identified an inhibitor 12-O-tricosanoylphorbol-20-acetate (hop-8), a novel ester of phorbol which was isolated from Ostodes katharinae of the family Euphorbiaceae, that inhibited the replication of wild-type HIV-1 and HIV-2 strains and drug-resistant strains broadly both in C8166 cells and PBMCs with low cytotoxicity and the EC₅₀ values ranged from 0.106 μM to 7.987 μM. One of the main mechanisms of hop-8 is to stimulate A3G expressing in HIV-1 producing cells and upregulate the A3G level in progeny virions, which results in reducing the infectivity of the progeny virus. This novel mechanism of hop-8 inhibition of HIV replication might represents a promising approach for developing new therapeutics for HIV infection.

The search for new molecular constructs that resemble the critical two-metal binding pharmacophore and the halo-substituted phenyl functionality required for HIV-1 integrase (IN) inhibition represents a vibrant area of research within drug discovery. As reported herein, we have modified our recently disclosed 1-[2-(4-fluorophenyl)ethyl]-pyrrole-2,5-dione scaffolds to design 35 novel compounds with improved biological activities against HIV-1. These new compounds show single-digit micromolar antiviral potencies against HIV-1 and low toxicity. Among of them, compound 9g and 15i had potent anti-HIV-1 activities (EC₅₀ < 5 μM) and excellent therapeutic index (TI, CC₅₀/EC₅₀ > 100). These two compounds have potential as lead compounds for further optimization into clinical anti-HIV-1 agents.

Aikeqing (AKQ) has been shown in clinical studies to improve quality of life of HIV/AIDS patients, but anti-HIV activity has not been determined. The SHIV-infected macaque is an important animal model for testing antiviral drugs. This study aimed to determine the anti-HIV activity of AKQ in chronically SHIV89.6-infected Chinese rhesus macaques. Nine Chinese rhesus macaques were inoculated intravenously with SHIV89.6 virus. At 11 weeks post-infection, the animals were arbitrarily divided into three groups: high-dose (AKQ 1.65 g/kg; n = 3), low-dose (AKQ 0.55 g/kg; n = 3), and control (water 1 mL/kg; n = 3). Treatment was administered by the intragastric gavage route once-daily for 8 weeks. Blood (5 mL) was collected biweekly. Viral loads were analyzed by real-time quantitative RT-PCR assays, and T cell counts were monitored by FACS analyses throughout the treatment. AKQ induced a persistent decline (P = 0.02) in plasma viral loads during treatment in the high-dose group compared with their baseline levels, and cessation of the therapy caused viral load rebound to the pretreatment levels. No significant difference (P = 0.06) was found in the plasma viral loads during treatment in the low-dose group. The CD4+ T cell counts and CD4/CD8 ratios remained at stable high levels during the treatment period. AKQ reduced plasma viral loads in the SHIV89.6-infected Chinese rhesus macaque model.

Ribosome inactivating proteins (RIPs) inhibit protein synthesis by depurinating the large ribosomal RNA and some are found to possess anti-human immunodeficiency virus (HIV) activity. Maize ribosome inactivating protein (RIP) has an internal inactivation loop which is proteolytically removed for full catalytic activity. Here, we showed that the recombinant active maize RIP protected chimeric simian-human immunodeficiency virus (SHIV) 89.6-infected macaque peripheral blood mononuclear cells from lysis ex vivo and transiently reduced plasma viral load in SHIV89.6-infected rhesus macaque model. No evidence of immune dysregulation and other obvious side-effects was found in the treated macaques. Our work demonstrates the potential development of maize RIP as an anti-HIV agent without impeding systemic immune functions.